Chemosensory olfactory assay for psychiatric disorders

ABSTRACT

The invention provides a method for diagnosing a psychiatric disorder in a patient. The method involves administering to the patient a plurality of concentrations of a chemosensory agent, identifying at least a 5 decismel change in the threshold amount of the chemosensory agent detected by the patient, and correlating the change in detection of the chemosensory agent with at least one psychiatric disorder.

This is a continuation of application Ser. No. 07/954,882, filed Sep.30, 1992, now abandoned.

BACKGROUND OF THE INVENTION

The ability to smell and, in part, the ability to taste is regulated bythe olfactory nerve system. The olfactory nerve system is complex andinterconnected with several systems in the brain. Olfactory receptorslocated in the nose are specialized bipolar neurons with ciliaprotruding into the mucous covering the epithelium. The axons of thebipolar neurons are packed into bundles that form connections in theolfactory bulb in the brain. The olfactory bulbs contain a rich supplyof neurotransmitters and neuromodulators. Neuromodulators includethyrotropin releasing hormone, substance P, enkephalin, dopamine,glutamate, and aspartate. The neurotransmitters include serotonin,acetylcholine and noradrenaline which are delivered to the bulbs fromcell bodies in other brain regions and are formed within the bulbs inthe terminal projections only. Central olfactory projections from thebulb interconnect the bulb to other areas of the brain, including thehippocampus, the hypothalamus, and the pyriform lobe.

There is an anatomical and biochemical connection between the olfactorysystem and the limbic system in the brain. The limbic system includesthe hippocampus and amygdala region, and is known as the emotionalcenter of the brain. The limbic regions have many synaptic contacts witholfactory bulbs. Many of the limbic structures and the olfactory bulbsare reciprocally interconnected in loop pathways that may be involved inthe regulation of brain emotional output.

There are several known disorders of taste and smell which affect thefunction of the olfactory system and which present major problems forthe patient. Chemosensory dysfunctions are usually described by thefollowing terms: ageusia (absence of taste), hypogeusia, (diminishedsensitivity of taste), dysgeusia (distortion of normal taste), anosmia(absence of smell), hyposmia (diminished sense of smell), and dysosmia(distortion of normal smell). These disorders cause modification of foodchoices and dietary habits, alter digestion, and the ability to detectnoxious gases and poisons. Overall, chemosensory disorders are chronicproblems that can reduce enjoyment and quality of life.

It is also known that neurological disorders involving damage to thebrain can also include a chemosensory dysfunction. For example, patientssuffering from Alzheimer's disease show a marked impairment in smellidentification which may be associated with senile plaques,neurofibrillary tangles, and reduced cholinergic activity in theolfactory bulb.

SUMMARY OF THE INVENTION

The invention provides a method for diagnosing psychiatric disorder in apatient by administering a plurality of concentrations of a chemosensoryagent, identifying at least a 5 decismel change in the threshold amountof at least one chemosensory agent detected by the patient andcorrelating that change with a diagnosis of at least one psychiatricdisorder. Patients, particularly those presenting with a chemosensorydysfunction, can be tested with various olfactory or gustatorychemosensory agents and the threshold level of detection of those agentsby the patient identified. Once identified, the threshold level ofdetection by the patient of at least one chemosensory agent is comparedwith the normal threshold amount and at least a 5 decismel change in thethreshold amount detected by the patient can indicate a chemosensory anda psychiatric disorder. This invention is based on my discovery that thechange in the threshold level of detection of a particular chemosensoryagent correlates with a psychiatric disorder which has been confirmed inindependent behavioral diagnosis. In a preferred version, thechemosensory agent is PE-phenol and the psychiatric disorder isdepression.

The invention also provides for a kit for diagnosing a psychiatricdisorder including: at least one chemosensory agent present inincreasing concentrations ranging from sub-threshold to suprathresholdamounts; optionally, a chart indicating the expected threshold amountsfor each of the chemosensory agents for each age group and sex ofpatients; and a chart of psychiatric disorders wherein the chartcorrelates a psychiatric disorder with at least a 5 decismel change inthe threshold amount of the chemosensory agent detected by the patient.The kit preferably contains at least 10 different concentrations of oneor more chemosensory agents and a chart correlating detection level ofseveral chemosensory agents with different psychiatric disorders asshown in Table V.

DETAILED DESCRIPTION OF THE INVENTION

The invention provides a method of diagnosing psychiatric disorders in ahuman patient who has a chemosensory dysfunction or disorder. Patientswith a chemosensory dysfunction have an alteration in the ability totaste or smell at least one chemosensory agent. A chemosensory agent isa compound that can be detected by a human's sense of smell or taste.Chemosensory dysfunctions or disorders are usually described by thefollowing terms: ageusia (absence of taste), hypogeusia, (diminishedsensitivity of taste), dysgeusia (distortion of normal taste), anosmia(absence of smell), hyposmia (diminished sense of smell), and dysosmia(distortion of normal smell). Using the method of the invention, achemosensory dysfunction in the detection of at least one chemosensoryagent correlates with and can be used to confirm a known psychiatricdiagnosis.

A patient is evaluated for a chemosensory dysfunction using standardchemosensory assays known to those of skill in the art. The patient'sability to detect the type and threshold amount of a chemosensory agentby the sense of taste or smell is measured. The preferred chemosensoryassays include the Smell Identification Test™, the Accusens T™ TasteTest, and unilateral threshold tests. The unilateral threshold test canbe conducted by standard methods and provides for olfactory testing withany number of chemosensory agents. The standards for unilateralthreshold testing in decismels, including the threshold concentrationsfor the chemosensory agents, can be obtained from OlfactoLabs, ElCerrito, Calif.

The chemosensory agent can be administered to the patient by smelling ortasting. The ability to detect the chemosensory agent in the right andleft nostrils is tested separately. Preferably, different concentrationsof the chemosensory agent are randomly given to the patient along withsamples that do not contain the chemosensory agent. Preferably, thepatient correctly identifies the chemosensory agent at a particularconcentration at least three times before the patient is scored ashaving correctly detected the chemosensory agent at that concentration.The threshold level of detection is the minimum concentration of thechemosensory agent detected by the patient.

Suitable examples of olfactory chemosensory agents includetrichloroethene, 1,2-dichloropropane, isobutyl isobutyrate, naphthalene,pyridine, 4-ethylphenol, phenylethyl methylethyl carbinol,(3-methyl-5-phenyl-3-pentanol) tetrahydrothiophene, isovaleric acid,trimethylamine, L-carvone, pentadecalactone, 1-pyrroline, 1,8-cineole,isobutyraldehyde, 16-androsten-3-one, thiophane, PE-phenol,(p-ethylphenol) CA-phenone, (α-chloro-acetophenone) as well as thechemosensory agents in the Smell Identification Test™. Suitablegustatory chemosensory agents include salt (NaCl), sucrose, hydrochloricacid (HCl), urea, and phenylthiocarbamide (PTC). The preferredchemosensory agent is PE-phenol.

The patient's threshold level for detecting a chemosensory agent isidentified and compared to the known threshold values for the same sexand age group. If the test samples containing a chemosensory agent areobtained from a commercial source, such as OlfactoLabs, El Cerrito,Calif., the samples are already calibrated in decismels and noconversion from absolute threshold concentration to decismels isnecessary. Alternatively, the normal threshold concentration can bedetermined by administering the same concentrations of the chemosensoryagent to a control group of at least 25 humans, who do not have achemosensory dysfunction, and calculating the mean thresholdconcentration detected by the group of 25 individuals. Anotheralternative is to refer to the known threshold value for thechemosensory agent that has been established previously and published byJ. Amoore et al., J. Appl. Toxicology, 3:272 (1983). A range of about-50 to +60 decismels is administered to the patient. A change of atleast 5 decismels (about a 2-fold concentration change) from the normalor expected value is considered significant and indicative of achemosensory dysfunction.

Odor thresholds are expressed on the decismel scale. The decismel scaleis constructed by setting the mean threshold concentration of achemosensory agent detected by the control group of 20 year olds at the0 value. A decismel is calculated by dividing the concentration of thechemosensory agent detected by the patient by the normal thresholdconcentration (using the published value or empirically determining thevalue) and then taking the logarithm of the quotient. The logarithm ofthe quotient is then multiplied by 20 to obtain the decismel value.Decismel values can be positive or negative. A positive decismel valueindicates the patient is less sensitive to the chemosensory agent, i.e.has a higher threshold detection concentration. A negative decismelvalue indicates that the patient is more sensitive to the compound, i.e.has a lower threshold detection concentration. An increase in thethreshold concentration value over the mean threshold concentrationvalue of 2-fold, corresponds to 6 decismels (or ds).

The suggested thresholds for hyposmia are 30 ds and functional anosmiaat 54 ds. A change of at least 5 ds from the normal or expected valuewas considered a significant change in the threshold level of detectionof the compound. Suitable corrections can also be made for the age ofthe patient. The threshold increase with aging is about 6 ds betweenages 20 and 40, and another 6 ds between 40 and 60.

The change in detection of sensitivity to at least one chemosensoryagent is correlated with a known psychiatric diagnosis by reference to achart, such as that provided in Table V. A change in detection of achemosensory agent correlates with a particular psychiatric disorder.For example, at least a 5 ds decrease in threshold detection level ofPE-phenol in the left nostril correlates with depression. The moresevere the depression, the greater the decrease in the thresholddetection level of PE-phenol.

Other psychiatric diagnoses can also correlate with a chemosensorydysfunction as follows: a decrease in the threshold detection level ofPE-phenol with depression; an increase in the threshold detection levelof thiophane detected in the right nostril and a decrease in the leftnostril with obsessive-compulsive personality disorder; an increase inthe threshold detection level for CA-phenone, pyridine, salt, andsucrose with a dependent personality disorder; a decrease in thethreshold detection level of salt and sucrose with anti-socialpersonality disorder; an increase in the threshold detection leveldetected of CA-phenone with atypical personality disorder; an increasein the threshold detection levels detected for pyridine and CA-phenonewith a passive-aggressive personality disorder; an increase in thethreshold detection level for carbinol with a somatization disorder; andan increase in the threshold detection level of CA-phenone and thiophanecorrelates with schizoid personality disorder.

Optionally, a psychiatric diagnosis of the patient can be confirmed bymethods known to those of skill in the art. Those methods can include apsychiatric interview, or administration of one or more writtenpsychological tests, or a combination of both. Suitable examples ofwritten psychological tests include the Minnesota MultiphasicPersonality Inventory I and II (MMPI-I and MMPI-II), the Millon ClinicalMultiaxial Inventory II™ (MCMI-II), the Beck Depression Inventory™. Thetests are administered and analyzed by methods known to those of skillin the art. Patients having a chemosensory dysfunction in the detectionof at least one chemosensory agent can also be given at least onewritten psychological test to confirm the psychiatric diagnosis whichcan then be analyzed by standard methodologies known to those of skillin the art.

Alternatively, the chemosensory assay can be used to confirm a suspectedpsychiatric disorder. The suspected psychiatric diagnosis can besuggested from the results of a psychiatric interview or byadministration of one or more written psychological tests, or both. Thechemosensory assay can be administered to a patient suspected of havinga psychiatric disorder and used to confirm the psychiatric disorder.

In the preferred method, the threshold detection level of PE-phenol in apatient is determined in both the left and right nostrils separately. Atleast 10 separate samples with different concentrations of PE-phenolranging from subthreshold to suprathreshold (i.e., -50 decismels to +60decismels) are intermixed with samples containing water only. Thepatient is asked to smell a water sample, followed by a PE-phenol sampleat a particular concentration, or in reverse order. The exposure withthe same concentration of PE-phenol is repeated at least three times.The patient preferably correctly identifies a sample of the PE-phenol atleast three times before a score indicating detection is marked for thatconcentration. The minimum concentration detected by the patient isidentified as the threshold level and, if necessary, this level can beconverted to decismels using the normal known or expected thresholdvalue for PE-phenol. A decrease of at least 5 ds in the thresholddetection level is correlated with depression, and the greater thedecrease in the threshold detection levels of the patient, the moresevere the depression. Optionally, the diagnosis of depression can beconfirmed by administering one psychological test, preferably the BeckDepression Inventory™.

The invention is also directed to a kit for diagnosing a psychiatricdisorder. The kit includes at least one chemosensory agent present in avariety of concentrations ranging from sub-threshold to suprathresholdamounts for that chemosensory agent. The normal or expected thresholdconcentration can be a known value published by Amoore et al., citedsupra., or can be determined empirically by testing a group of normalindividuals with a plurality of concentrations of the chemosensory agentand calculating the means threshold concentration. Alternatively, theconcentrations of the chemosensory agent can be supplied alreadyconverted to decismels, as described previously. A sub-threshold amountis a concentration of the chemosensory agent below the normal orexpected threshold concentration for that chemosensory agent. Asuprathreshold amount is a concentration of the chemosensory agentgreater than the threshold amount. The kit preferably contains about10-64 different concentrations of the chemosensory agent ranging fromabout -50 decismels to +60 decismels.

Suitable examples of chemosensory agents include one or more of thefollowing compounds: trichloroethene, 1,2-dichloropropane, isobutylisobutyrate, naphthalene, pyridine, 4-ethylphenol, phenylethylmethylethyl carbinol, tetrahydrothiophene, isovaleric acid,trimethylamine, L-carvone, pentadecalactone, 1-pyrroline, 1,8-cineole,isobutyraldehyde, 16-androsten-3-one, thiophane, PE-phenol, CA-phenone.Suitable gustatory chemosensory agents include salt (NaCl), sucrose,hydrochloric acid (HCl), urea, and phenylthiocarbamide (PTC). Thepreferred chemosensory agent is PE-phenol.

The kit can also optionally include a chart indicating the normalthreshold concentration values for at least chemosensory agent. Thethreshold concentration of the chemosensory agent detected by thepatient is compared to the normal or expected value on the chart. Atleast a 5 decismel change in the threshold level detected by the patientof a chemosensory agent can be identified and correlated with apsychiatric disorder or central or peripheral nerve dysfunction.

The kit also includes a chart correlating at least a 5 decismel changein the threshold detection of a chemosensory agent with a psychiatricdisorder. The chart includes the following correlations between changesin threshold levels of the detection for chemosensory agents withpsychiatric diagnoses: a decrease in the threshold detection level ofPE-phenol with depression; an increase in the threshold detection levelof thiophane detected in the right nostril and a decrease in the leftnostril with obsessive-compulsive personality disorder; an increase inthe threshold detection levels for CA-phenone, pyridine, salt, andsucrose with a dependent personality disorder; a decrease in thethreshold detection level of salt and sucrose with anti-socialpersonality disorder; an increase in the threshold detection leveldetected of CA-phenone with atypical personality disorder; an increasein the threshold detection levels detected for pyridine and CA-phenonewith a passive-aggressive personality disorder; an increase in thethreshold detection level for carbinol with a somatization disorder; andan increase in the threshold detection level of CA-phenone and thiophanewith schizoid personality disorder.

The preferred kit contains 10 different concentrations of each of thefollowing chemosensory agents: PE-phenol, thiophane, pyridine,CA-phenone, carbinol, salt, sucrose and phenothiocarbimide (PTC). Thepreferred kit also contains a chart showing the normal thresholdconcentration values for each of these chemosensory agents for each sexand age group and optionally indicating hyposmia, anosmia, andhyperosmia. The preferred kit also contains a chart, such as shown inTable V, correlating at least a 5 decismel change in the threshold leveldetected of a chemosensory agent with a psychiatric disorder.

EXAMPLE I

Forty-six consecutive patients presenting to the Smell and TasteTreatment and Research Foundation with chemosensory dysfunction wereevaluated for olfactory and gustatory dysfunction as well aspsychological dysfunction. The patients' mean age was 40 years with aslight majority being men (61%), n=28. Presenting chemosensorycomplaints include: hyposmia, hypogeusia 96% (44), dysgeusia 20% (9) andphantageusia 37% (17). These problems were associated with diverseetiologies, as shown in Table I.

                  TABLE I                                                         ______________________________________                                        ETIOLOGY OF CHEMOSENSORY DISORDER                                             (n = 46)                                                                                     Patients                                                                             Percentage                                              ______________________________________                                        Post-Traumatic   21       46%                                                 Post-Infectious  16       35%                                                 Allergic Rhinitis                                                                              12       26%                                                 Polyposis         6       13%                                                 Medication-Induced                                                                              2        4%                                                 Other            20       43%                                                 ______________________________________                                    

The patients underwent psychiatric and neurological histories andexaminations. They completed extensive olfactory and gustatory testsincluding the Smell Identification Test™, unilateral threshold testing,including carbinol, PE phenol, PD lactone, cineole, thiophane, pyridine,and CA phenone, and the Accusens T™ Taste Test (see Table II).

                  TABLE II                                                        ______________________________________                                        CHEMOSENSORY TESTS                                                                       Unilateral Olfactory                                               Gustatory  Threshold Tests                                                                              Olfactory                                           ______________________________________                                        NaCl       Carbinol       UPSIT - Formal                                      Sucrose    PD Lactone     Pennsylvania                                        HCl        Cineole        Olfactory Test                                      Urea       Thiophane                                                          PTC        Pyridine                                                                      CA Phenone                                                         ______________________________________                                    

Written psychological testing including the Minnesota MultiphasicPersonality Inventory II™ (MMPI-II), the Millon Clinical MultiaxialInventory II™ (MCMI-II), and Beck Depression Inventory™.

The Smell Identification Test™ was obtained from Sensonics, Inc. ofHaddenfield, N.J., and was conducted according to standard methodologiesas described in the Smell Identification Test™ Administration Manual.Briefly, patients were tested for smell identification and sensitivityto 40 stimuli using scratch and sniff cards. Each subject rated thefragrance samples by scratching with a pencil included with the testcards, sniffing, and then identifying the odorant as one of fourchoices. A label could be repeatedly scratched as needed before movingto the next odorant and returning to previous odors was allowed.

The results of the patient's score on the Smell Identification Test™were evaluated by reference to the established normal values for age andgender provided in the Smell Identification Test™ Administration Manualon pages 19 and 20. The patient's total number of correct responses(maximum of 40) was established by use of the test's scoring key. Thepatient's test score is located in the far left hand column of Table 1for women and Table 2 for men. The age group is located along the top ofthe table and the subject's percentile score is read at the intersectionof test score row and age group column. The percentile value reflectsthe percentage of normal patients having that score.

A diagnosis for an olfactory dysfunction is made by identifying whetherthe person's test score falls within the anosmia (total inability toperceive odor) or microsomia range (decreased smell ability). Generally,scores falling in the following ranges are indicative of smelldysfunction:

    ______________________________________                                        Smell Identification                                                          Test Score       Olfactory Diagnosis                                          ______________________________________                                        0-5              Probable malingering                                          6-19            Total anosmia                                                20-33            Microsomia (males only)                                      20-34            Microsomia (females only)                                    34-40            Normosmia (males only)                                       35-40            Normosmia (females only)                                     ______________________________________                                    

The unilateral threshold test was conducted according to standardmethods as described by J. Amoore et al., Rhinology, 21:49-54 (1983).Briefly, the patient's ability to detect increasing amounts of carbinol,PD-lactone, cineole, thiophane, pyridine, (PE-phenol), and CA-phenone inthe left and right nostrils was tested. The standards in decismels wereobtained from OlfactoLabs, El Cerrito, Calif. For example, the thresholdlevel of PE phenol detected by a patient was determined by presentingthe patient with 64 different bottles of different concentrations ofPE-phenol. The patients were presented with bottles of differentconcentrations compared to the blank and asked to identify the bottlewith the substance. The patient was presented with the bottles in randomorder and needed to correctly identify the substance three times inorder to identify the patient's threshold concentration. The level atwhich the patients in the study detected each of the compounds wascompared to known or expected values. The standard samples fromOlfactoLabs were already calibrated in decismels. If the amount detectedby the patient was lower than the expected values, the patient was moresensitive to the compound and detected the chemosensory agent at anegative decismel value. If the amount detected known was greater thanthe expected value, the patient was less sensitive to the compound anddetected the chemosensory agent at a positive decismel value.

Odor thresholds are expressed on the "decismel scale". The meanthreshold concentration of a chemosensory agent detected by a controlgroup of 20-year olds is set at the 0 value. A decismel is calculated bydividing the concentration of the chemosensory agent detected by thepatient to the normal threshold concentration (using the published valueor empirically determining the value) and then taking the logarithm ofthe quotient. The logarithm of the quotient is then multiplied by 20 toobtain the decismel value. Decismel values can be positive or negative.A positive decismel value indicates the patient is less sensitive to thechemosensory agent, i.e. has a higher threshold detection concentration.A negative decismel value indicates that the patient is more sensitiveto the compound, i.e. has a lower threshold detection concentration. Anincrease in the threshold concentration value over the mean thresholdconcentration value of twofold corresponds to 6 decismels. The suggestedthresholds for hyposmia are 30 ds and of functional anosmia at 54 ds.The normal mean threshold values for each chemosensory agent are knownand can be used to convert the threshold concentration into decismels. Achange of at least 5 ds from the expected value was considered asignificant change in the threshold level of detection of the compound.

The Accusens T Test® was conducted according to standard methods asdescribed by the Accusens T™ Taste Function Kit Manual. Briefly, theability of the patients to taste sodium chloride (NaCl), sucrose,hydrochloric acid (HCl), urea, and phenylthiocarbamide (PTC) wasevaluated by the patients tasting solutions containing increasingamounts of the compound.

The ability of the patients to detect and recognize the type andintensity of the solution was measured. Two drops of each of threesolutions was placed on a patient's tongue successively. Two of threesolutions were water and one of the solutions was either salty (NaCl),sweet (sucrose), sour (HCl) and bitter (PTC). Three differentconcentrations of salt, sucrose and HCl were tested. The PTC test wasthe last test performed. The patient was instructed to identify whichone of the three solutions was different, whether it was salty, sweet,sour or bitter, and to estimate the degree of the taste on a scale of 1to 100. All three judgments must be correct for diagnosis of normaltaste. If the patient could not detect correctly the different tastantor recognize each tastant, the next higher concentration of the tastantswas tested in the same manner until the patient correctly identified thetastants. The patient's responses were compared to established valuesfor normal taste detection and recognition provided in the test kit. Anyfailure to detect or recognize the tastants is indicative that thepatient has hypogeusia.

If the patient correctly detects and recognizes all of the tastants butgives intensity responses less than 5%, then a second test is done.Patients taste each of three different concentrations of the NaClsolution, sucrose solution and HCl solution and rate the intensity ofeach of the solutions. Responses considered normal for the lowestconcentration are 5% to 15%, responses considered normal for the middleconcentration are 10% to 30% and responses considered normal for thehighest concentration are 25% to 50%. Any response lower than the lowerpercentage of the ranges noted above is abnormal and indicative ofhypogeusia.

The patients also were evaluated for psychiatric disorders using theMMPI-II, the MCMI-II, and the Beck Depression Inventory. The MMPI-II isavailable from National Computer Systems and is administered accordingto standard methodologies as described in Psychological Assessment withthe MMPI, A. Friedman et al., editor, Laurence Erlbaum Assoc.,publishers (1989) at pages 40-53. The MMPI-II provides a basis fordiagnosis of hypochondriasis, depression, anxiety disorder,passive-aggressive personality, psychosis, borderline personalities,schizoid disorder, paranoia, as described in Psychological Assessmentwith the MMPI, cited supra., at pages 150-198. The MCMI-II is availablefrom National Computer Systems and is administered according to standardmethods described in the Test Administration Instruction Booklet. Theresults from the MCMI-II provide a basis for diagnosis of DSMIIIR-AxisII diagnosis. The Beck Depression Inventory is administered according tostandard methodologies as described in the Test AdministrationInstruction Booklet. The results from the Beck Depression Inventoryprovide a measure of the severity of the depression.

The MMPI-II and the MCMI-II provide a basis for a diagnosis of aDSMIII-R Axis I or DSMIII-R Axis II disorder. The DSMIII-R Axis Idisorders include generalized anxiety disorder and a chronic form ofdepression known as dysthymia. The DSMIII-R Axis II disorders includeobsessive-compulsive personality disorder, narcissistic personalitydisorder, personality disorder N.O.S.; histrionic personality disorder;dependent personality disorder; schizoid personality disorder;antisocial personality disorder; atypical personality disorder;passive-aggressive personality disorder; and somatization disorder. Thesymptoms and diagnosis of these psychological disorders are described inthe American Psychiatric Association's Diagnostic and Statistical Manualof Mental Disorders, 3rd edition, Wash, D.C. (1987), which is herebyincorporated by reference. The Beck Depression Inventory measures energyloss, problems thinking, as well as other factors and provides a basisfor determining the severity of a depression.

Diagnosis of the psychiatric disorder is made based upon the results ofMMPI-II or MCMI-II tests and psychiatric interview. As shown in TableIV, some of the 46 patients were classified into more than Axis I orAxis II diagnosis.

The results from the olfactory and gustatory tests and psychologicaltests were analyzed statistically by standard methods, as described inApplied Depression Analysis and Other Multivariant Methods, and acorrelation between the chemosensory test data and the diagnosisindicated by the psychological test data was conducted. The data wereanalyzed employing univariate methods for simple summary statistics andby applying correlation methods to examine statistical relationshipsamong the study variables. Although the conventional level ofsignificance (p<0.05) was initially used to select the groups ofvariables exhibiting significance, since there were multiple testsinvolved, the significance levels were further subjected to BonferroniCorrection as described by Kleinbaum et al., Applied Digression Analysisand Other Multivariant Methods, DWS Kent Publishing, Boston, Mass.(1988), and only those correlations meeting the Bonferroni criterionwere reported as being significant.

The results shown in Tables III and IV indicate that patients exhibitinga chemosensory dysfunction also exhibited the symptoms of at least oneand sometimes more than one psychiatric disorder. As defined by theresults of the MMPI-II or MCMI-II, 33% (15) had a DSMIIIR axis Idiagnosis; 96% (44) met a total of 74 DSMIIIR axis II diagnoses; and 4%(2) were felt to be psychiatrically normal and did not meet a DSMIIIRaxis I or axis II diagnosis. (See Tables III and IV.)

                  TABLE III                                                       ______________________________________                                        AXIS I DIAGNOSIS                                                              (n = 46)                                                                                    Patients                                                                             Percentage ± S.E.*                                    ______________________________________                                        Generalized Anxiety                                                                           10       22% ± 12                                          Disorder                                                                      Dysthymia        9       20% ± 12                                          Other Axis I    11                                                            Diagnoses                                                                     Total number of Axis I Diagnoses                                                                     = 30                                                   Percentage of patients with at                                                                       = 33% ± 14                                          least one Axis I Diagnosis                                                    ______________________________________                                         *Standard Error of the percentage for 95% confidence interval.           

                  TABLE IV                                                        ______________________________________                                        AXIS II DIAGNOSIS                                                             (n = 46)                                                                                   Patients                                                                             Percentage ± S.E.*                                     ______________________________________                                        Obsessive      16       35% ± 14                                           Compulsive P.D.                                                               Narcissistic P.D.                                                                            10       22% ± 12                                           Personality    10       22% ± 12                                           Disorder N.O.S.                                                               Histrionic P.D.                                                                               9       20% ± 12                                           Dependent P.D.  8       17% ± 11                                           Schizoid P.D.   7       15% ± 10                                           Other Axis I   14                                                             Diagnoses                                                                     ______________________________________                                         *Standard Error of the percentage for 95% confidence interval.           

The most frequent axis I diagnoses were generalized anxiety disorder 22%(n=10); dysthymia (9); and somatization disorder 11% (5) (Table III).The most frequent DSMIIIR axis II diagnoses were obsessive-compulsivepersonality disorder, 35% (n=16); narcissistic personality disorder, 22%(10); personality disorder not otherwise specified, 22% (10); andhistrionic personality disorder, 20% (9). (See Table IV.)

In general, the greater perceived severity of the olfactory problem, themore likely the patient has an DSMIIIR axis II obsessive-compulsivepersonality disorder (p<0.018). This is predictable since the obsessivenature of this psychiatric disorder would tend to amplify any unexpectedsomatic complaints. Eighty percent of subjects had chemosensorycomplaints for less than 7 years. Longer duration of chemosensorycomplaints is correlated to DSMIIIR axis II abnormalities includingavoidant personality disorder (p<0.001), passive-aggressive personalitydisorder (p<0.007), and borderline personality disorder (p<0.001), aswell as DSMIIIR axis I schizophrenic disorders (p<0.01) and paranoiddisorders (p<0.001). The longer the chemosensory complaints persist, themore likely there is a co-existing DSMIIIR axis I major depression(p<0.001). This is further suggested by the correlation of increase inlevels (p<0.008). The longer the problem exists, the worse thedepression as measured by the Beck Depression Inventory (p<0.001).

In male subjects, the correlation between major depression (p<0.0005),energy loss (p<0.003), and problems thinking (p<0.002) was especiallyprominent. As duration of chemosensory symptoms lengthens, otherpsychiatric disorders appear in men including axis I diagnosis ofschizophrenia (p<0.009), axis II diagnoses of avoidant personalitydisorder (p<0.0005), borderline personality disorder (p<0.0005), andpassive-aggressive personality disorder (p<0.007).

                                      TABLE V                                     __________________________________________________________________________           Depression                                                                           Obsessive-    Anti-         Passive                                    (Beck Inv.)                                                                          Compulsive                                                                           Dependent                                                                            Social Atypical                                                                             Agressive                                                                            Somatization                                                                         Schizotypal           __________________________________________________________________________    PTC                  (unable)*                                                                     p < .007                                                 PE-Phenol                                                                     Right  ↓ p < .016*                                                                   ↓ p < .008*                                              Left   ↓ p < .007                                                      UPSIT                                            ↓ p < .02**           Thiophane                                                                     Right         ↑ p < .0005*                        ↑ p < .006                    ↑ p < .006                                                Left          ↓ p < .009                                               Pyridine                                                                      Right                                     ↑ p < .01                     Left                 ↑ p < .011*    ↑ p < .008                    Ca-Phenone                                                                    Right                ↑ p < .007*                                                                           ↑ p < .001                                                                     ↑ p < .001                                                                            ↑ p < .001      Left                               ↑ p < .001                                                                     ↑  p < .001                                                                           ↑ p < .001      Carbinol                                                                      Right                                            ↑ p < .008             Left                                             ↑ p < .001             Salt Taste           H p < .007                                                                           Hy p < .01                                        Sucrose Taste        H p < .017*                                                                          Hy p < .01                                        __________________________________________________________________________     *Females only                                                                 **Males only                                                                  At least a 5 decismel decrease in the threshold amount detected from the      normal value for same age group and gender                                    At least a 5 decismel increase in the threshold amount detected from the      normal value for same age group and gender.                                   H = Hypogeusia                                                                HY = Hypergeusia                                                         

The results in Table V also show that changes in specific chemosensorysensitivities correlate with diagnoses of psychiatric disorders.Depression and the severity of depression correlates with at least a 5decismel decrease in the threshold level of detection of PE phenol inthe left nostril and also in the right nostril in women. Patientsdiagnosed with an obsessive-compulsive disorder show at least a 5decismel (about 2-fold) increase in the threshold sensitivity forthiophane in the right nostril and at least a 5 decismel (about 2-fold)decrease in the threshold level detected in the left nostril. Womendiagnosed with the obsessive-compulsive disorder also show a decrease inthe threshold level of PE phenol detected in the right nostril. Womendiagnosed with dependent personality disorder show at least a 5 decismel(about 2-fold) increase in the threshold level of detection of pyridinein the left nostril and an increase in the threshold level detected ofCA phenone in the right nostril, as well as hypogeusia for tastingsucrose and an inability to detect PTC. Both men and women diagnosedwith dependent personality disorder show an increase in the thresholdtaste level for salt. Patients diagnosed with antisocial personalitydisorder show a decreased threshold taste level for salt and sucrose.Patients diagnosed with atypical personality disorder show at least 5decismel increase in the threshold level for CA phenone. Patientsdiagnosed with passive-aggressive personality disorder show at least 5decismel increase in the threshold detection level for pyridine and CAphenone. Patients diagnosed with a somatization disorder show at least 5decismel increase in the threshold level of detection of carbinol and adecrease in male patients of the UPSIT score. Patients diagnosed with aschizoid personality disorder show increase in the threshold detectionlevels for CA phenone and thiophane. Thus, patients presenting with aspecific chemosensory dysfunction can also be diagnosed for apsychiatric dysfunction using the chemosensory assays.

The results confirm a high incidence of mood disorders and extensivechemosensory testing procedures allow detection of additionalpsychiatric diagnoses not previously reported to co-exist withchemosensory complaints. The recognition of this co-morbidity isimportant for clinicians for the proper diagnosis and treatment ofpatients with chemosensory disorders.

All patents and publications cited herein are hereby incorporated byreference. While the present invention has been described in connectionwith the preferred embodiment thereof, it will be understood manymodifications will be readily apparent to those skilled in the art, andthis application is intended to cover any adaptations or variationsthereof. It is manifestly intended this invention be limited only by theclaims and equivalents thereof.

What is claimed is:
 1. A method of diagnosing depression in a patienthaving a chemosensory dysfunction, comprising:administering a pluralityof concentrations of p-ethylphenol to the patient to determine thepatient's threshold detection level for p-ethylphenol; comparing thethreshold detection level of the patient with a standard thresholdamount for p-ethylphenol detected by a normal person of the same sex andage as the patient; identifying at least a 5 decismel decrease in thethreshold detection level of the patient compared to the standardthreshold amount for p-ethylphenol; and correlating the at least 5decismel decrease in the threshold detection level with a diagnosis ofdepression in the patient.
 2. A method for confirming depression in apatient, comprising:administering a plurality of concentrations ofp-ethylphenol to the patient to determine the patient's thresholddetection level for p-ethylphenol; comparing the threshold detectionlevel with a standard threshold amount for p-ethylphenol detected by anormal person of the same sex and age as the patient; identifying atleast a 5 decismel decrease in the threshold detection level of thepatient compared to the standard threshold amount for p-ethylphenol;correlating the at least 5 decismel decrease in the threshold detectionlevel with a diagnosis of depression in the patient; and administering astandard written psychological test diagnostic for depression to confirmthe diagnosis of depression in the patient by the p-ethylphenol test.